Osteoporosis International

, Volume 30, Issue 1, pp 103–114 | Cite as

Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies

  • T.N. Poly
  • M.M. Islam
  • H.-C. Yang
  • C.C. Wu
  • Y.-C.(.J.). LiEmail author
Original Article



We performed a meta-analysis of relevant studies to quantify the magnitude of the association between proton pump inhibitors (PPIs) and risk of hip fracture. Patients with PPIs had a greater risk of hip fracture than those without PPI therapy (RR 1.20, 95% CI 1.14–1.28, p < 0.0001). These results could be taken into consideration with caution, and patients should also be concerned about the inappropriate use of PPIs.


Proton pump inhibitors (PPIs) are generally considered as first-line medicine with great safety profile, commonly prescribed for gastroesophageal reflux disease (GERD) and peptic ulcer disease. However, several epidemiological studies documented that long-term use of PPIs may be associated with an increased risk of hip fracture. Although, the optimal magnitude of the hip fracture risk is still undetermined. We, therefore, performed a meta-analysis of relevant studies to quantify the magnitude of the association between PPIs and risk of hip fracture.


We collected relevant articles using MEDLINE, EMBASE, Google Scholar, and Web of Science from January 1, 1990, to March 31, 2018. We included only the large (n ≥ 500) observational studies with a follow-up duration of at least one year in which the hip fracture patients were identified by a standard procedure. Two of the authors extracted data from each included study independently according to a standardized protocol.


A total of 24 observational studies with 2,103,800 participants (319,568 hip fracture patients) met all the eligibility criteria. Patients with PPIs had a greater risk of hip fracture than those without PPI therapy (RR 1.20, 95% CI 1.14–1.28, p < 0.0001). An increased association was also observed in both low and medium doses of PPI taken and hip fracture risk (RR 1.17, 95% CI 1.05–1.29, p = 0.002; RR 1.28, 95% CI 1.14–1.44, p < 0.0001), but it appeared to be even greater among the patients with higher dose (RR 1.30, 95% CI 1.20–1.40, p < 0.0001). Moreover, the overall pooled risk ratios were 1.20 (95% CI 1.15–1.25, p < 0.0001) and 1.24 (95% CI 1.10–1.40, p < 0.0001) for the patients with short- and long-term PPI therapy, respectively, compared with PPI non-users.


Our results suggest that PPI use is significantly associated with an increased risk of hip fracture development, which is not observed in H2RA exposure. Physicians should, therefore, exercise caution when considering a long-term PPI treatment to their patients who already have an elevated risk of hip fracture. In addition, patients should be concerned about the inappropriate use of PPIs; if necessary, then, they should continue to receive it with a clear indication.


Bone fracture Gastroesophageal reflux disease Hip fracture Osteoporosis Proton pump inhibitors 



This work was financially supported by the “TMU Research Center of Cancer Translational Medicine” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan and the Health and Welfare surcharge of tobacco grants MOHW-106-TDU-B-144001.

Compliance with ethical standards

Conflicts of interest

All the authors (Tahmina Nasrin Poly, Md. Mohaimenul Islam, Hsuan-Chia Yang, Chieh Chen Wu, Yu-Chuan (Jack) Li) declare that they do not have any conflict of interest.

Supplementary material

198_2018_4788_MOESM1_ESM.docx (325 kb)
ESM 1 (DOCX 325 kb)


  1. 1.
    Reyes C, Formiga F, Coderch M, Hoyo J, Ferriz G, Casanovas J, Monteserín R, Brotons C, Rojas M, Moral I (2013) Use of proton pump inhibitors and risk of fragility hip fracture in a Mediterranean region. Bone 52:557–561CrossRefGoogle Scholar
  2. 2.
    Jordan K, Cooper C (2002) Epidemiology of osteoporosis. Best Pract Res Clin Rheumatol 16:795–806CrossRefGoogle Scholar
  3. 3.
    Bass E, French DD, Bradham DD, Rubenstein LZ (2007) Risk-adjusted mortality rates of elderly veterans with hip fractures. Ann Epidemiol 17:514–519CrossRefGoogle Scholar
  4. 4.
    Bakken MS, Engeland A, Engesæter LB, Ranhoff AH, Hunskaar S, Ruths S (2014) Risk of hip fracture among older people using anxiolytic and hypnotic drugs: a nationwide prospective cohort study. Eur J Clin Pharmacol 70:873–880CrossRefGoogle Scholar
  5. 5.
    Elaine WY, Bauer SR, Bain PA, Bauer DC (2011) Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med 124:519–526CrossRefGoogle Scholar
  6. 6.
    Islam MM, Poly TN, Walther BA, Dubey NK, Ningrum DNA, Shabbir S-A, Li Y-CJ (2018) Adverse outcomes of long-term use of proton pump inhibitors: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 30:1395–1405CrossRefGoogle Scholar
  7. 7.
    Wan QY, Wu XT, Li N, Du L, Zhou Y (2018) Long-term proton pump inhibitors use and risk of gastric cancer: a meta-analysis of 926 386 participants. Gut 2018.Google Scholar
  8. 8.
    Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA (2015) Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. PLoS One 10:e0128004CrossRefGoogle Scholar
  9. 9.
    Nochaiwong S, Ruengorn C, Awiphan R, Koyratkoson K, Chaisai C, Noppakun K, Chongruksut W, Thavorn K (2017) The association between proton pump inhibitor use and the risk of adverse kidney outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant 33:331–342CrossRefGoogle Scholar
  10. 10.
    Sun S, Cui Z, Zhou M, Li R, Li H, Zhang S, Ba Y, Cheng G (2017) Proton pump inhibitor monotherapy and the risk of cardiovascular events in patients with gastro-esophageal reflux disease: a meta-analysis. Neurogastroenterol Motil 29:e12926CrossRefGoogle Scholar
  11. 11.
    Batchelor R, Gilmartin JFM, Kemp W, Hopper I, Liew D (2017) Dementia, cognitive impairment and proton pump inhibitor therapy: a systematic review. J Gastroenterol Hepatol 32:1426–1435CrossRefGoogle Scholar
  12. 12.
    Filion KB, Chateau D, Targownik LE, Gershon A, Durand M, Tamim H, Teare GF, Ravani P, Ernst P, Dormuth CR (2013) CNODES Investigators. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis. Gut 63(4):552–8.Google Scholar
  13. 13.
    Adams AL, Black MH, Zhang JL, Shi JM, Jacobsen SJ (2014) Proton-pump inhibitor use and hip fractures in men: a population-based case-control study. Ann Epidemiol 24:286–290CrossRefGoogle Scholar
  14. 14.
    De Vries F, Cooper A, Cockle S, van Staa T-P, Cooper C (2009) Fracture risk in patients receiving acid-suppressant medication alone and in combination with bisphosphonates. Osteoporos Int 20:1989–1998CrossRefGoogle Scholar
  15. 15.
    Chen C-H, Lin C-L, Kao C-H (2016) Gastroesophageal reflux disease with proton pump inhibitor use is associated with an increased risk of osteoporosis: a nationwide population-based analysis. Osteoporos Int 27:2117–2126CrossRefGoogle Scholar
  16. 16.
    O’Connell MB, Madden DM, Murray AM, Heaney RP, Kerzner LJ (2005) Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med 118:778–781CrossRefGoogle Scholar
  17. 17.
    Ngamruengphong S, Leontiadis GI, Radhi S, Dentino A, Nugent K (2011) Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am J Gastroenterol 106:1209–1218CrossRefGoogle Scholar
  18. 18.
    Ye X, Liu H, Wu C, Qin Y, Zang J, Gao Q, Zhang X, He J (2011) Proton pump inhibitors therapy and risk of hip fracture: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 23:794–800CrossRefGoogle Scholar
  19. 19.
    Zhou B, Huang Y, Li H, Sun W, Liu J (2016) Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int 27:339–347CrossRefGoogle Scholar
  20. 20.
    Hussain S, Siddiqui AN, Habib A, Hussain MS, Najmi AK (2018) Proton pump inhibitors’ use and risk of hip fracture: a systematic review and meta-analysis. Rheumatology international. 2018 Aug 29:1-6.24.Poly TN, Islam MM, Yang HC, Li YC. Non-steroidal anti-inflammatory drugs and risk of Parkinson’s disease in the elderly population: a meta-analysis. Eur J Clin Pharmacol 1:1–0.Google Scholar
  21. 21.
    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269CrossRefGoogle Scholar
  22. 22.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188CrossRefGoogle Scholar
  23. 23.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ: Br Med J 327:557–560CrossRefGoogle Scholar
  24. 24.
    Poly TN, Islam MMR, Yang H-C, Li Y-CJ (2018) Non-steroidal anti-inflammatory drugs and risk of Parkinson’s disease in the elderly population: a meta-analysis. Eur J Clin Pharmacol:1–10Google Scholar
  25. 25.
    Vestergaard P, Rejnmark L, Mosekilde L (2006) Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 79:76–83CrossRefGoogle Scholar
  26. 26.
    Ding J, Heller DA, Ahern FM, Brown TV (2014) The relationship between proton pump inhibitor adherence and fracture risk in the elderly. Calcif Tissue Int 94:597–607CrossRefGoogle Scholar
  27. 27.
    Lee J, Youn K, Choi N-K, Lee J-H, Kang D, Song H-J, Park B-J (2013) A population-based case–control study: proton pump inhibition and risk of hip fracture by use of bisphosphonate. J Gastroenterol 48:1016–1022CrossRefGoogle Scholar
  28. 28.
    Pouwels S, Lalmohamed A, Souverein P, Cooper C, Veldt B, Leufkens H, de Boer A, van Staa T, de Vries F (2011) Use of proton pump inhibitors and risk of hip/femur fracture: a population-based case-control study. Osteoporos Int 22:903–910CrossRefGoogle Scholar
  29. 29.
    Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD (2008) Use of proton pump inhibitors and risk of osteoporosis-related fractures. Can Med Assoc J 179:319–326CrossRefGoogle Scholar
  30. 30.
    Khalili H, Huang ES, Jacobson BC, Camargo CA, Feskanich D, Chan AT (2012) Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMj 344:e372CrossRefGoogle Scholar
  31. 31.
    Chiu HF, Huang YW, Chang CC, Yang CY (2010) Use of proton pump inhibitors increased the risk of hip fracture: a population-based case–control study. Pharmacoepidemiol Drug Saf 19:1131–1136CrossRefGoogle Scholar
  32. 32.
    Yang Y-X, Lewis JD, Epstein S, Metz DC (2006) Long-term proton pump inhibitor therapy and risk of hip fracture. Jama 296:2947–2953CrossRefGoogle Scholar
  33. 33.
    Kaye JA, Jick H (2008) Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 28:951–959CrossRefGoogle Scholar
  34. 34.
    Lai S-W, Lin C-H, Lin C-L, Liao K-F (2018) Proton pump inhibitors therapy and the risk of hip fracture in older people in Taiwan. Eur Geriatr Med 9:169–174CrossRefGoogle Scholar
  35. 35.
    Lenihan CR, Nair SS, Vangala C, Ramanathan V, Montez-Rath ME, Winkelmayer WC (2017) Proton pump inhibitor use and risk of hip fracture in kidney transplant recipients. Am J Kidney Dis 69:595–601CrossRefGoogle Scholar
  36. 36.
    Lin S-M, Yang S-H, Liang C-C, Huang H-K (2018) Proton pump inhibitor use and the risk of osteoporosis and fracture in stroke patients: a population-based cohort study. Osteoporos Int 29:153–162CrossRefGoogle Scholar
  37. 37.
    Fraser L, Leslie W, Targownik L, Papaioannou A, Adachi J, Group CR (2013) The effect of proton pump inhibitors on fracture risk: report from the Canadian Multicenter Osteoporosis Study. Osteoporos Int 24:1161–1168CrossRefGoogle Scholar
  38. 38.
    Elaine WY, Blackwell T, Ensrud KE, Hillier TA, Lane NE, Orwoll E, Bauer DC (2008) Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int 83:251–259CrossRefGoogle Scholar
  39. 39.
    Corley DA, Kubo A, Zhao W, Quesenberry C (2010) Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology 139:93–101CrossRefGoogle Scholar
  40. 40.
    Gray SL, LaCroix AZ, Larson J, Robbins J, Cauley JA, Manson JE, Chen Z (2010) Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women’s Health Initiative. Arch Intern Med 170:765–771CrossRefGoogle Scholar
  41. 41.
    Cea Soriano L, Ruigómez A, Johansson S, García Rodríguez LA (2014) Study of the association between hip fracture and acid-suppressive drug use in a UK primary care setting. Pharmacotherapy 34:570–581CrossRefGoogle Scholar
  42. 42.
    Torvinen-Kiiskinen S, Tolppanen AM, Koponen M, Tanskanen A, Tiihonen J, Hartikainen S, Taipale H (2018) Proton pump inhibitor use and risk of hip fractures among community-dwelling persons with Alzheimer's disease—a nested case-control study. Aliment Pharmacol Ther 47:1135–1142CrossRefGoogle Scholar
  43. 43.
    Abrahamsen B, Vestergaard P (2013) Proton pump inhibitor use and fracture risk—effect modification by histamine H1 receptor blockade. Observational case–control study using National Prescription Data. Bone 57:269–271CrossRefGoogle Scholar
  44. 44.
    Wang L, Li M, Cao Y, Han Z, Wang X, Atkinson EJ, Liu H, Amin S (2017) Proton pump inhibitors and the risk for fracture at specific sites: data mining of the FDA adverse event reporting system. Sci Rep 7:5527CrossRefGoogle Scholar
  45. 45.
    Datta H, Ng W, Walker J, Tuck S, Varanasi S (2008) The cell biology of bone metabolism. J Clin Pathol 61:577–587CrossRefGoogle Scholar
  46. 46.
    Mizunashi K, Furukawa Y, Katano K, Abe K (1993) Effect of omeprazole, an inhibitor of H+, K+-ATPase, on bone resorption in humans. Calcif Tissue Int 53:21–25CrossRefGoogle Scholar
  47. 47.
    Hansen KE, Jones AN, Lindstrom MJ, Davis LA, Ziegler TE, Penniston KL, Alvig AL, Shafer MM (2010) Do proton pump inhibitors decrease calcium absorption? J Bone Miner Res 25:2786–2795CrossRefGoogle Scholar
  48. 48.
    Joo MK, Park J-J, Lee BJ, Kim JH, Yeon JE, Kim JS, Byun KS, Bak Y-T (2013) The effect of a proton pump inhibitor on bone metabolism in ovariectomized rats. Mol Med Rep 7:1267–1272CrossRefGoogle Scholar
  49. 49.
    Kocsis I, Arató A, Bodánszky H, Szönyi L, Szabó A, Tulassay T, Vásárhelyi B (2002) Short-term omeprazole treatment does not influence biochemical parameters of bone turnover in children. Calcif Tissue Int 71:129–132CrossRefGoogle Scholar
  50. 50.
    Sharara AI, El-Halabi MM, Ghaith OA, Habib RH, Mansour NM, Malli A, El Hajj-Fuleihan G (2013) Proton pump inhibitors have no measurable effect on calcium and bone metabolism in healthy young males: a prospective matched controlled study. Metabolism 62:518–526CrossRefGoogle Scholar
  51. 51.
    Agréus L, Svärdsudd K, Talley NJ, Jones MP, Tibblin G (2001) Natural history of gastroesophageal reflux disease and functional abdominal disorders: a population-based study. Am J Gastroenterol 96:2905–2914CrossRefGoogle Scholar
  52. 52.
    Scarpignato C, Gatta L, Zullo A, Blandizzi C (2016) Effective and safe proton pump inhibitor therapy in acid-related diseases—a position paper addressing benefits and potential harms of acid suppression. BMC Med 14:179CrossRefGoogle Scholar
  53. 53.
    Grimes DA, Schulz KF (2012) False alarms and pseudo-epidemics: the limitations of observational epidemiology. Obstet Gynecol 120:920–927CrossRefGoogle Scholar
  54. 54.
    Leontiadis GI, Moayyedi P (2014) Proton pump inhibitors and risk of bone fractures. Curr Treat Options Gastroenterol 12:414–423CrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Authors and Affiliations

  • T.N. Poly
    • 1
    • 2
  • M.M. Islam
    • 1
    • 2
  • H.-C. Yang
    • 2
  • C.C. Wu
    • 1
    • 2
  • Y.-C.(.J.). Li
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Graduate Institute of Biomedical Informatics, College of Medical Science and TechnologyTaipei Medical UniversityTaipeiTaiwan
  2. 2.International Center for Health Information Technology (ICHIT)Taipei Medical UniversityTaipeiTaiwan
  3. 3.Department of DermatologyWan Fang HospitalTaipeiTaiwan
  4. 4.TMU Research Center of Cancer Translational MedicineTaipeiTaiwan

Personalised recommendations